Long-Term Pain Relief: The Long, Troubled Search

Look back through a decade of headlines, and you’ll understand why the FDA’s new drug advisory panel held its collective nose last week when it voted to recommend Purdue Pharma’s application for a new formulation of oxycodone hydrochloride (OxyContin).

Purdue says OxyContin 2.0 is harder to chew, sniff, snort, inject, and otherwise turn into a heavy-duty recreational drug than its 14-year-old predecessor.

However, this may not be much of an accomplishment, considering that it takes little more than a good set of teeth or a mortar and pestle to turn OxyContin 1.0 into a potentially lethal, one-dose jolt of a drug whose effect is similar to heroin’s.

“The tamper-resistant properties of the reformulated OxyContin are limited," an FDA staff review concluded. "However, the tamper-resistance characteristics of reformulated OxyContin may provide an advantage over the currently available OxyContin."

The problem: as valuable as it has been for cancer patients and others who suffer debilitating, chronic pain, OxyContin and other prescription painkillers have become the nation’s entree of choice into the world of drug abuse.

According to the 2009 National Drug Threat Assessment, more first-time drug abusers (2.1 million) start on prescription opioid pain relievers than any other drug – including marijuana.

Yes, that means OxyContin and its cousins have replaced pot as the traditional gateway to Hell. Which is saying something, when you consider that 47% of American adults say they’ve smoked marijuana at some time in their lives.

To get a feel for the problem, visit Google News and run a search on OxyContin. Reports from police departments and drug rehab centers around the country tell sorry tales of a dangerous, addictive drug that has infested many communities – particularly in Appalachia and other rural areas, where OxyContin has taken on the nickname “Hillbilly Heroin.”

In retrospect, we may be repeating a scenario that developed more than a century ago, when pharmaceutical companies began an organized but still-unsuccessful effort to produce a safe, powerful, long-lasting, nonaddictive painkiller.

The initial push came from Bayer AG, whose brilliant chemist, Felix Hoffman, changed the analgesic industry forever in the course of 11 remarkable days in 1897, when he synthesized two new painkillers. One was acetylsalicylic acid, which Bayer marketed as Aspirin. The other was diacetylmorphine, which Bayer marketed under the brand name Heroin (yes, it was trademarked, with a capital “H”).

Heroin was a smash hit as a cough suppressant and allegedly nonaddictive substitute for morphine – which was the unfortunate drug of choice for treating pneumonia and tuberculosis in the days before doctors knew what caused the diseases or had antibiotics to fight them.

But Heroin turned out to be as dangerous as it was powerful. Within a decade, Heroin addiction and abuse were serious public health problems, and scientists realized that the drug was actually metabolized as morphine – with all of morphine’s problems and dangers.

In 1910, Bayer withdrew Heroin from the over-the-counter market. Meanwhile, with drug addiction rampant, Congress enacted the Harrison Act in 1914 to control the sale of opioids as prescription drugs, and in 1924 Congress banned heroin outright.

Yes, by that time, Bayer had lost the right to the Heroin and Aspirin trademarks as part of Germany’s reparations under the 1919 Treaty of Versailles.

Aspirin (which eventually lost its capital “A”) went on to be the most successful drug in history – as an analgesic, anti-inflammatory, antipyretic, hangover cure and most recently as an antiplatelet agent.

But scientists were still looking for a powerful morphine substitute that wasn’t as dangerous as heroin (now with a small “h”).

One possibility was oxycodone. With heroin discredited, German scientists developed oxycodone in 1916, synthesizing it from thebaine, a chemical cousin to morphine and codeine. Originally they thought oxycodone, too, might have less addictive properties than morphine, but it turned out to have most of the same dangers and limitations.

That landscape remained virtually unchanged until 1995, when Purdue Pharma won FDA approval for OxyContin – a novel formulation of oxycodone hydrochloride that contained a relatively large opioid payload but released it slowly and steadily over a period of 12 hours.

This was a major breakthrough in the treatment of chronic pain, which requires maintaining a continuous level of analgesic in the bloodstream, and a major failing of morphine, straight oxycodone, and similar drugs that typically last only two to three hours. In fact, the “Contin” in OxyContin comes from the term “continuous.”

For its intended purpose, OxyContin was an immediate success, clinically and financially, with sales eventually reaching $2 billion a year.

But the drug’s very labeling contained what amounted to instructions for abusing it – a warning that chewing or crushing the drug could release the entire dose of oxycodone at one time, a dose that was potentially life-threatening if it was swallowed, snorted, or injected.

Meanwhile, Purdue Pharma engaged in an aggressive – and according to prosecutors and plaintiffs in a variety of lawsuits -- irresponsible marketing campaign to convince doctors that it was somehow safer and less addictive than other drugs and to prescribe it for conditions less serious than long-term, debilitating chronic pain.

By 2001, it was becoming apparent that OxyContin abuse was a major public health issue in many parts of the country. That resulted in an ongoing series of skirmishes between Purdue, the FDA, the Drug Enforcement Administration and doctors who prescribed the drug heavily. A variety of public and private legal actions were filed against Purdue, topped off by a federal investigation and prosecution.

In 2007, the company and three of its current and former executives pleaded guilty to misleading the public about OxyContin’s addiction and abuse potential. They agreed to pay an unprecedented $634.5 million in fines, and the three executives were sentenced to community service, but got no jail time.

At the same time, the company agreed to pay $19.5 million to 26 states and the District of Columbia to settle complaints that it encouraged physicians to overprescribe OxyContin.

Shortly after that, the state of Kentucky filed suit against Purdue on behalf of three eastern counties hit hardest by OxyContin abuse. That suit was removed from the Kentucky state courts – where it might have been resolved quickly on terms favorable to the plaintiffs – and consolidated with dozens of other, mostly unrelated lawsuits, in U.S. District Court in New York.

Meanwhile, Purdue maintains that it has mended its ways, and over the years, the FDA has mandated increasingly strict labeling for OxyContin.

Still, there was little enthusiasm for Purdue’s latest application at Thursday’s joint meeting of the FDA’s Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee.

Purdue says the new resin-coated formulation makes it harder to crush into a fine powder and thus more difficult to extract the oxycodone payload for recreational use. And officials say that when the new version of the drug is dissolved in water, it produces a gel that makes snorting the drug more difficult.

Members of the advisory panel complained that Purdue offered no proof – in the form of controlled trials – showing that the new formula is safer. Still, most agreed that making the pills harder to crush, chew, or dissolve into liquid was a good idea.

In fact, the FDA has been encouraging manufacturers to develop
long-lasting painkillers that can’t be pounded, ground up, dissolved or
tweaked for a quick hit.

"Clearly the old [formulation] is worse than the new, although I think the difference is relatively small," said panelist Randall Flick, MD, an anesthesiologist at the Mayo Clinic who voted for approval.

The panel’s 14-4 vote in favor of the application is advisory only. The FDA doesn’t have to follow the committee’s advice, but it usually does.

Ironically, if the FDA acts soon, the new OxyContin would reach the market before a long-awaited competitor from King Pharmaceuticals, whose application for FDA approval of a secure, time-release version of oxycodone was sent back for more work but is likely to be revived in 2010.

Even a competitor to OxyContin won’t solve the real problem, which is this: a century after the first modern attempt to synthesize one, science is still looking for a safe, effective, long-term painkiller.